Project Summary: Neural plasticity is central to learning and memory. By tuning the strength of signaling between connected neurons, their response properties can be altered to subsequent experiences in order to adapt to the environment. Neural plasticity is therefore required for basic animal survival. However, not all learning is beneficial ? we also make maladaptive associations and habits that can contribute to a wide variety of neuropsychiatric conditions. These include drug addiction, depression, anxiety, and post-traumatic stress disorder, among others. Unfortunately, despite decades of research there has been little to no progress on treating most of these conditions. Therefore, understanding how the underlying plasticity is formed, maintained, and disrupted is critical for developing a new set of approaches to combat these disorders. About a decade ago, it was discovered that injection of a small peptide called ZIP into the brain could disrupt the maintenance of established memories. However, recently the mechanism of this reagent has been called into serious doubt. Nonetheless, ZIP injection has repeatedly been shown to destabilize established memories; therefore, identifying the real mechanism would lend valuable insight to the design and construction of a new set of molecular approaches to modulating memories. My preliminary data has identified that ZIP destabilizes memories through induction of macropinocytosis, presumably through removal of surface glutamate receptors from the synapse. In this proposal, I aim to first elucidate which synaptic proteins are affected by ZIP injection and use this to engineer a suite of molecular and viral-genetic reagents to specifically disrupt or stabilize memories in targeted cell types. I will then apply these methods to unique ensembles encoding rewarding or aversive experiences to demonstrate how exclusive modulation of plasticity in defined populations can control behavior. Lastly, I will show how this technology can be used to reverse the maladaptive plasticity that contributes to a variety of behavioral symptoms in a mouse model of chronic stress and depression. The toolkit developed in this proposal would revolutionize our understanding and control of learning and memory, which could have a major impact on the field of neuroscience.